This is a revision of a K23 application targeting the development of a clinical investigator in an area of pressing public health significance. A growing literature indicates that mental illness can be associated with an increased prevalence of obesity, diabetes mellitus, dyslipidemia and cardiovascular disease, in some cases building on already epidemic rates in the general population. Factors contributing to these problems, including medication effects can be studied using reliable and validated methodologies that rarely are applied in psychiatric research. This K23 will allow the Candidate to develop unique and needed expertise in techniques for studying alterations in whole-body glucose and lipid metabolism, and the regulation of body composition and weight. The career development plan is integrated with a related research plan that aims to study the effects of multi-class polypharmacy (antipsychotic plus valproate) on sensitive measures of insulin sensitivity, lipid metabolism and fat mass. Motivating this plan, the treatment of schizophrenia commonly utilizes multi-class polypharmacy, with up to 35% of atypical antipsychotic prescriptions accompanied by co-prescription of valproate. Due in part to increases in polypharmacy, psychotropic costs (e.g. Missouri Medicaid) have nearly doubled in the last 10 years, with similar increases nationwide. Polypharmacy is associated with increased risk for medication interactions, poorer compliance, confounding of medication effects, and can lead to additional polypharmacy to treat side effects. Glucoregulatory abnormalities, diabetes, dyslipidemia, and increased adiposity have all been associated with antipsychotic treatment, and the addition of valproate can further disturb glucose and lipid metabolism and weight regulation. Although sensitive methods are available, studies have not addressed the metabolic consequences of this common type of polypharmacy. The Candidate will combine and extend the knowledge of two Cosponsors to develop expertise in the assessment of lipid metabolism, insulin sensitivity and weight regulation. Schizophrenia patients suffer nearly twice the rate of cardiovascular death as the general population, and changes in lipid metabolism are strongly associated with changes in cardiovascular risk. Current NIH guidelines recommend reduction of lipids as the main intervention for prevention of cardiovascular disease. This project aims to evaluate the effects of olanzapine and risperidone in combination with valproate on glucose and lipid metabolism, abdominal fat, and total body fat using available gold standard methodologies. The aims will be addressed in non-diabetic schizophrenia patients chronically treated with olanzapine or risperidone who will be randomized to receive either concomitant valproate versus no additional treatment. Relevant data are critically needed to target basic research, identify long-term cardiovascular risks, and plan therapeutic interventions.